US8951958B2 - Purification of caspofungin intermediates - Google Patents
Purification of caspofungin intermediates Download PDFInfo
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- US8951958B2 US8951958B2 US13/637,386 US201113637386A US8951958B2 US 8951958 B2 US8951958 B2 US 8951958B2 US 201113637386 A US201113637386 A US 201113637386A US 8951958 B2 US8951958 B2 US 8951958B2
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- compound
- pneumocandin
- solvent
- general formula
- caspofungin
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- 238000000746 purification Methods 0.000 title claims abstract description 12
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 title claims description 13
- 108010020326 Caspofungin Proteins 0.000 title claims description 9
- 229960003034 caspofungin Drugs 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- -1 1-methylimidazol-2-yl Chemical group 0.000 claims description 4
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 108010069514 Cyclic Peptides Proteins 0.000 abstract description 8
- 102000001189 Cyclic Peptides Human genes 0.000 abstract description 8
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 108010049047 Echinocandins Proteins 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012535 impurity Substances 0.000 description 17
- DQXPFAADCTZLNL-FXDJFZINSA-N pneumocandin B0 Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 DQXPFAADCTZLNL-FXDJFZINSA-N 0.000 description 15
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 0 C=C(N)CC(O)[C@@H]1NC(=O)[C@H]([C@H](O)C(O)C2=CC=C(O)C=C2)NC(=O)[C@@H]2CC(O)CN2C(=O)[C@H](C(C)O)NC(=O)[C@@H]([1*]N)CC(O)C([2*]S)NC(=O)[C@@H]2C(O)CCN2C1=O Chemical compound C=C(N)CC(O)[C@@H]1NC(=O)[C@H]([C@H](O)C(O)C2=CC=C(O)C=C2)NC(=O)[C@@H]2CC(O)CN2C(=O)[C@H](C(C)O)NC(=O)[C@@H]([1*]N)CC(O)C([2*]S)NC(=O)[C@@H]2C(O)CCN2C1=O 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 108010064760 Anidulafungin Proteins 0.000 description 2
- DFQUSLQYURJBIT-MFKXNLKNSA-N C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 DFQUSLQYURJBIT-MFKXNLKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 108010021062 Micafungin Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 description 2
- 229960003348 anidulafungin Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BJBUEDPLEOHJGE-IUYQGCFVSA-N cis-3-hydroxy-D-proline zwitterion Chemical group O[C@H]1CCN[C@H]1C(O)=O BJBUEDPLEOHJGE-IUYQGCFVSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 description 2
- 229960002159 micafungin Drugs 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IPMHTGKXJQHTQV-YWVCOZMLSA-N 6-(trans-4-hydroxy-l-proline)-pneumocandin bo Chemical compound C1([C@@H](O)C(O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](O)[C@@H](O)CC(C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 IPMHTGKXJQHTQV-YWVCOZMLSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241001460671 Glarea lozoyensis Species 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 241000144175 Lophium arboricola Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 108010090182 cilofungin Proteins 0.000 description 1
- ZKZKCEAHVFVZDJ-MTUMARHDSA-N cilofungin Chemical compound C1=CC(OCCCCCCCC)=CC=C1C(=O)N[C@@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2C[C@H](C)[C@H](O)[C@H]2C(=O)N[C@H](O)[C@H](O)C1 ZKZKCEAHVFVZDJ-MTUMARHDSA-N 0.000 description 1
- 229950007664 cilofungin Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- XDRVAZAFNWDVOE-UHFFFAOYSA-N cyclohexylboronic acid Chemical compound OB(O)C1CCCCC1 XDRVAZAFNWDVOE-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 108010062092 echinocandin B Proteins 0.000 description 1
- FAUOJMHVEYMQQG-HVYQDZECSA-N echinocandin B Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCC\C=C/C\C=C/CCCCC)[C@@H](C)O)=CC=C(O)C=C1 FAUOJMHVEYMQQG-HVYQDZECSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- RTMQLLLPNLXDSP-LORNMRFGSA-N pneumocandin a2 Chemical compound C1([C@@H](O)C(O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)NCCCC(C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 RTMQLLLPNLXDSP-LORNMRFGSA-N 0.000 description 1
- XYZCJMODJVDCJD-WGFNUKEGSA-N pneumocandin a4 Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N2C[C@H](C)[C@H](O)[C@H]2C(=O)NCCCC(C(N[C@H](C(=O)N2C[C@H](O)C[C@H]2C(=O)N1)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)CC1=CC=C(O)C=C1 XYZCJMODJVDCJD-WGFNUKEGSA-N 0.000 description 1
- CAUDURDUCQQHDE-UVQGGVJESA-N pneumocandin b2 Chemical compound C1([C@@H](O)C(O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)NCCCC(C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 CAUDURDUCQQHDE-UVQGGVJESA-N 0.000 description 1
- QDHVQAJPCGRBRI-ULQDJTMQSA-N pneumocandin do Chemical compound C1([C@@H](O)C(O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](O)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCCC(C)CC(C)CC)[C@H](O)CC(N)=O)=CC=C(O)C=C1 QDHVQAJPCGRBRI-ULQDJTMQSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the present invention relates to a method for the purification of cyclopeptides.
- Cyclopeptides are polypeptides in which the terminal amine and carboxyl groups form an internal peptide bond.
- Several cyclopeptides are known for their advantageous medicinal properties.
- An excellent example of this is the class of echinocandins which are potent antifungals.
- Cyclopeptides can be naturally occurring compounds but may also be obtained by total synthesis or by synthetic or genetic modification of naturally occurring or naturally produced precursors; the latter class is referred to as semi synthetic cyclopeptides.
- Examples of medicinally useful echinocandins are the cyclic hexapeptides anidulafungin, caspofungin, cilofungin and micafungin which are useful in treating fungal infections especially those caused by Aspergillus, Blastomyces, Candida, Coccidioides and Histoplasma .
- Anidulafungin, caspofungin and micafungin are all semi synthetic cyclopeptides derivable from naturally occurring echinocandins such as for instance echinocandin B, pneumocandin A 0 or pneumocandin B 0 .
- caspofungin (1) from fermentatively obtained pneumocandin B 0 (2) (with R 1 ⁇ C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ) in both compounds), is a process wherein removal of impurities is an important issue.
- pneumocandin B 0 A multitude of structurally related impurities occurring during fermentation of pneumocandin B 0 (2, R 1 ⁇ C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 )
- Examples are compounds having an additional methyl function (such as pneumocandin A 0 , pneumocandin A 1 , pneumocandin A 2 , pneumocandin A 3 , pneumocandin A 4 , pneumocandin A 5 , pneumocandin A 6 ), compounds lacking one or two hydroxyl groups (such as pneumocandin B 1 , pneumocandin B 2 , pneumocandin B 5 , pneumocandin B 6 , pneumocandin E 0 ), compounds having a 4-hydroxy proline rather than a 3-hydroxy proline moiety (pneumocandin C 0 ), compounds having additional hydroxyl groups (such as pneumocandin D 0 , pneumo
- R 1 is C(O)R 3 with R 3 is C 9 -C 21 alkyl, C 9 -C 21 alkenyl, C 1 -C 10 alkoxyphenyl, C 1 -C 10 alkoxynaphthyl or C 1 -C 10 alkoxyterphenyl and wherein R 2 is benzimidazol-2-yl, benzothiazol-2-yl, 1-methylimidazol-2-yl, 4-methoxyphenyl or phenyl and wherein X is O or H,H, comprising the steps of:
- the compounds of the first aspect of the present invention are characterized in quite different chemical behavior caused by the introduction of a thio-functionality instead of a hydroxyl group. Still further away from the pneumocandin core are those molecules wherein also an amide functionality (X ⁇ O) is replaced with an amine group (X ⁇ H, H). These differences as compared to pneumocandin B 0 , will lead to differences in charge, hydrophilicity and molecular weight. Since any or all of these characteristics play a pivotal role in successful separation of the C 0 impurity from pneumocandin B 0 , it is to be expected that major changes in the substrates will disturb the separation behavior.
- R 1 is C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 .
- group R 2 is phenyl and preferably the silicate is silica gel.
- a solution of crude compound (3) as defined above is brought into contact with a silicate. After a period of time sufficient for allowing adsorption, the liquid phase is separated from the silicate. Appropriate periods of time are from 1 min to 24 h, preferably from 5 min to 12 h. Removal of the liquid phase can be achieved using various techniques such as filtration, centrifugation, evaporation and the like.
- Suitable solvent are any solvents in which the substrate dissolves with a preference for alcohols such as for example ethanol and methanol. Elution from the silicate can be effected by applying solvents or solvent mixtures. Preferably a solvent mixture is applied comprising an alcohol, an ester and water.
- the mixture of silicate and crude compound (3) obtained above is applied to a column of silicate prior to elution with solvent or solvent mixture. It was found that this increases separation between the various components, notably compounds (3) and (5)
- the solvents or solvent mixtures used in the second embodiment may be the same as mentioned in the first embodiment.
- a solvent mixture is used comprising an acid, for example from 0.1 to 10%, preferably from 0.2 to 5%, most preferably from 0.5 to 2% (v/v).
- Suitable acids are small molecular weight acids such as hydrochloric acid, sulfuric acid, formic acid and the like.
- a preferred acid is acetic acid.
- a composition comprising a compound of general formula (3), from 0.0001% to 0.2% by weight of a compound of general formula (4) and/or from 0.0001% to 0.2% by weight of a compound of general formula (5), wherein R 1 is C(O)R 3 with R 3 is C 9 -C 21 alkyl, C 9 -C 21 alkenyl, C 1 -C 10 alkoxyphenyl, C 1 -C 10 alkoxynaphthyl or C 1 -C 10 alkoxyterphenyl and wherein R 2 is benzimidazol-2-yl, benzothiazol-2-yl, 1-methylimidazol-2-yl, 4-methoxyphenyl or phenyl and wherein X is O or H,H.
- R 1 is C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 and/or R 2 is phenyl.
- FIG. 1 is the UPLC analysis of the purification of compound (3) with R 1 is C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 , R 2 is phenyl and X is oxygen on silica gel 60 using ethyl acetate/methanol/water (85/9/6, v/v/v) as eluting solvent.
- X-axis column fractions in bed volumes (bed volume is 100 mL and fractions of 1 ⁇ 8 bed volume were analyzed).
- Left Y-axis measured peak area for compound (3; ⁇ ).
- Right Y-axis measured peak area for compounds (4; ⁇ ) and (5; ⁇ ) with R 1 , R 2 and X as defined above.
- FIG. 2 is the UPLC analysis of the purification of compound (3) with R 1 is C(O)(CH 2 ) 8 CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 , R 2 is phenyl and X is H,H on silica gel 60 using ethyl acetate/methanol/water/acetic acid (76/17/7/1, v/v/v/v) as eluting solvent.
- X-axis column fractions in bed volumes (bed volume is 100 mL and fractions of 1 ⁇ 8 bed volume were analyzed).
- Left Y-axis measured peak area for compound (3; ⁇ ).
- Right Y-axis measured peak area for compounds (4; ⁇ ) and (5; ⁇ ) with R 1 , R 2 and X as defined above.
- Pneumocandin B 0 was obtained by fermentation of Glarea Lozoyensis ( Zalerion arboricola ) as described in WO 2000/008197. Commercially available reagents were used as received unless mentioned otherwise. Solvents were dried over 3 ⁇ molecular sieves. UPLC analysis was carried out using an Acquity UPLC BEH C18 1.7 ⁇ m (2.1*150 mm) column (Art nr 186002353) under the following conditions:
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| Application Number | Priority Date | Filing Date | Title |
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| EP10158204 | 2010-03-29 | ||
| EP10158204.7 | 2010-03-29 | ||
| EP10158204 | 2010-03-29 | ||
| PCT/EP2011/054351 WO2011120842A1 (en) | 2010-03-29 | 2011-03-22 | Purification of caspofungin intermediates |
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| US20130018171A1 US20130018171A1 (en) | 2013-01-17 |
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| US (1) | US8951958B2 (de) |
| EP (1) | EP2552941B1 (de) |
| CN (1) | CN102947327B (de) |
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| HU (1) | HUE029822T2 (de) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9636407B2 (en) | 2012-11-20 | 2017-05-02 | Fresenius Kabi Usa, Llc | Caspofungin acetate formulations |
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| US20140005355A1 (en) * | 2011-01-03 | 2014-01-02 | Biocon Limited | Process for preparation of caspofungin acetate and intermediates |
| CN105164146B (zh) * | 2013-05-02 | 2019-06-28 | 灿盛制药有限公司荷兰公司 | 分离卡泊芬净的方法 |
| CN104163855B (zh) * | 2013-05-16 | 2017-10-17 | 重庆圣华曦药业股份有限公司 | 一种卡泊芬净中间体及其盐的分离纯化方法 |
| CN104250289A (zh) * | 2013-06-28 | 2014-12-31 | 博瑞生物医药技术(苏州)有限公司 | 一种纽莫康定b0的分离纯化方法 |
| CN112110991A (zh) * | 2014-12-24 | 2020-12-22 | 上海天伟生物制药有限公司 | 一种含氮杂环六肽前体的组合物及其制备方法和用途 |
| CN105218645B (zh) * | 2015-10-14 | 2018-08-07 | 成都雅途生物技术有限公司 | 一种高纯度高收率的卡泊芬净杂质c0的制备方法 |
| CN110655557A (zh) * | 2018-06-28 | 2020-01-07 | 浙江医药股份有限公司新昌制药厂 | 一种纽莫康定b0丝氨酸类似物的分离纯化方法 |
| CN109400680A (zh) * | 2018-12-07 | 2019-03-01 | 成都雅途生物技术有限公司 | 一种卡泊芬净前体pneumocandinB0的结晶纯化方法 |
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| WO2002083713A2 (en) | 2001-04-12 | 2002-10-24 | Merck & Co., Inc. | Echinocandin process |
| WO2009142761A1 (en) | 2008-05-21 | 2009-11-26 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Caspofungin bo free of caspofungin co |
| WO2009158034A1 (en) | 2008-06-25 | 2009-12-30 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Caspofungin free of caspofungin impurity a |
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| JP2003510245A (ja) | 1998-08-07 | 2003-03-18 | メルク エンド カムパニー インコーポレーテッド | 抗生物質の製造方法 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002083713A2 (en) | 2001-04-12 | 2002-10-24 | Merck & Co., Inc. | Echinocandin process |
| WO2009142761A1 (en) | 2008-05-21 | 2009-11-26 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Caspofungin bo free of caspofungin co |
| US20090291996A1 (en) * | 2008-05-21 | 2009-11-26 | Ferenc Korodi | Caspofungin free of caspofungin Co |
| WO2009158034A1 (en) | 2008-06-25 | 2009-12-30 | Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag | Caspofungin free of caspofungin impurity a |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9636407B2 (en) | 2012-11-20 | 2017-05-02 | Fresenius Kabi Usa, Llc | Caspofungin acetate formulations |
Also Published As
| Publication number | Publication date |
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| ES2596103T3 (es) | 2017-01-05 |
| WO2011120842A1 (en) | 2011-10-06 |
| CN102947327B (zh) | 2017-06-13 |
| CN102947327A (zh) | 2013-02-27 |
| EP2552941A1 (de) | 2013-02-06 |
| EP2552941B1 (de) | 2016-07-20 |
| HUE029822T2 (en) | 2017-04-28 |
| SI2552941T1 (sl) | 2016-11-30 |
| US20130018171A1 (en) | 2013-01-17 |
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